Richard L. Borison

A path-analytical approach to differentiate between direct and indirect drug effects on negative symptoms in schizophrenic patients. A re-evaluation of the North American risperidone study.

The hypothesis that differences in drug effects of risperidone and haloperidol on negative symptoms in schizophrenia are secondary to effects on positive, extrapyramidal, and depressive symptoms was investigated by means of an analysis of the data from the USA-Canada risperidone double-blind randomized clinical trial of 523 chronic schizophrenic patients. Regression analyses in the total sample and within treatment groups confirmed a strong relationship between changes in negative symptoms and the other variables studied (R2=0.50−0.51,p<0.001). Only depressive symptoms did not contribute significantly to these results (p>0.10). Path analysis showed that the greater mean change (p<0.05) of negative symptoms with risperidone compared to haloperidol could not be fully explained by correlations with favourable effects on positive and extrapyramidal symptoms. The relationship between shift in extrapyramidal symptoms and shift in negative symptoms failed to reach statistical significance; however, there was a clear tendency in the expected direction in both treatment groups.

A comparison of venlafaxine, trazodone, and placebo in major depression.

A double-blind, placebo-controlled trial was undertaken to compare the safety and efficacy of venlafaxine and trazodone in patients with major depression. Two hundred twenty-five patients entered an initial 6-week treatment phase, and 149 completed it. Ninety-six patients who were responders continued in a 1-year, double-blind, long-term phase during which they received the same medication and doses they had during the short-term phase. Both active treatments were significantly more effective than placebo on some measures during the short-term study, but venlafaxine produced more improvement in the cognitive disturbance and retardation factors on the Hamilton Rating Scale for Depression. Trazodone was more effective against the sleep disturbance factor. Patients on venlafaxine were most likely to enter the long-term phase and to remain in the trial longest. The side effect profiles of the three treatment groups were compared. Venlafaxine was most likely to cause nausea, whereas trazodone was associated with the most dizziness and somnolence.

Postsynaptic efficacy of dopamine: Possible suppression by estrogen ☆

Abstract Behavioral, neurochemical and pharmacological data have indicated a possible interaction between estrogen and dopamine. Treatment of ovariectomized rats with estradiol benzoate (EB) prior to testing for stereotyped behavior shifted the dose response curve for apomorphine to the right, increasing the median effective dose from 0.38 to 0.65 mg/kg. Ovariectomized rats treated chronically with EB for 14 days were more responsive than oil injected controls when challenged with apomorphine on the seventh day after cessation of EB treatment. Similarly long term ovariectomized rats also display an enhanced response to apomorphine in terms of development of stereotyped behavior. The reduced response to apomorphine following acute EB (3 days) can be interpreted as a possible decrease in either the number of affinity of dopamine receptors. Moreover the enhanced response to apomorphine after cessation of chronic EB treatment (14 days) may be explained on the basis of a decrease in the postsynaptic efficacy of dopamine during chronic treatment with EB, which is then over compensated for upon withdrawal from chronic treatment. The increased sensitivity to apomorphine in long term ovariectomized animals is also consistent with the chronic suppression of dopamine efficacy in the intact female animal.

Enkephalins and nigrostriatal function

Unilatera1 lesions of the substantia nigra were made with 6-hydroxydopamine in rats. In this model, drugs such as naloxone, which block endogenous enkephalin receptors, potentiated agents with postsynaptic dopaminergic actions, while antagonizing agents with presynaptic dopaminergic actions. Drugs which increase brain enkephalin content (d-phenylalanine or methionine-enkephalin) antagonized postsynaptically active agents and potentiated presynaptic agents. Naloxone also reversed reserpine-induced parkinsonism in rats. Separate pre-and postsynaptic enkephalinergic neurons thus seem to modulate nigrostriatal function.

Treatment approaches in Gilles de la Tourette syndrome.

The neurological disorder Gilles de la Tourette syndrome is most often treated with the receptor blocker haloperidol, which also produces multiple side-effects, including the risk for tardive dyskinesia. In placebo control double-blind studies, two other neuroleptic drugs, fluphenazine and trifluoperazine, were found to be as efficaceous as haloperidol, but with fewer side-effects. In other studies, clonidine was shown to be equally efficaceous with haloperidol, but did not produce adverse central nervous system side-effects. To treat the extrapyramidal side-effects accompanying the treatment of Tourette syndrome with neuroleptic agents, amantadine and benztropine were compared in a crossover study. It was demonstrated that amantadine is a superior agent in treating the side effects of haloperidol treatment in Tourette syndrome. The use of lithium was without significant action upon lessening the tics of Tourette syndrome.

The Oral Dose-Effect Relationship for Fluvoxamine: a Fixed-Dose Comparison Against Placebo in Depressed Outpatients

This 7- to 8-week, multicenter, randomized, double-blind, placebo-controlled study was performed to determine the dose-effect relationship and minimum effective dose for fluvoxamine maleate in a titrated fixed-dose study of major depressive disorder. Gradual titration over 2 weeks to fixed maintenance doses was employed to minimize dropout due to initial side effects. The study enrolled 600 outpatients, male and female, age 18-65, meeting DSM-III-R criteria for major depressive disorder. A 13-item subscore of the standard 21-Item Hamilton Depression Scale was used to minimize the possible contribution of known side effects from serotonin reuptake inhibitors to the overall HAM-D score. Secondary efficacy assessments included the HAM-D retardation factor, HAM-D depressed mood item, CGI-severity of illness item, and SCL depression factor. Fluvoxamine (50-150 mg/day) was therapeutically effective and well tolerated during 6 weeks of therapy. Based on the HAM-D depressed mood item, efficacy was dose dependent. The minimum effective dose was 50 mg/day. Fluvoxamine maleate shows dose-related effectiveness in the acute treatment of major depressive disorder.

Changes in peripheral benzodiazepine receptors in patients with panic disorder and obsessive-compulsive disorder

Peripheral benzodiazepine (BDZ) receptors were investigated through the binding of the specific ligand 3H-PK-11195 to platelet membranes, in 17 patients suffering from panic disorder (PD) and in 16 patients affected by obsessive-compulsive disorder (OCD). The results, showing that the density (Bmax) of peripheral BDZ receptors was significantly lower in patients with PD than in controls or OC patients, suggest that the number of platelet BDZ receptors varies with different anxiety disorders and that perhaps this marker may be beneficial in differentiating some subtypes of these disorders.

Clinical efficacy of serotonin-dopamine antagonists relative to classic neuroleptics

&NA; Serotonin‐dopamine antagonists (SDAs) offer the possibility of improved treatment of schizophrenia compared with conventional neuroleptics and have superior safety profiles. Clinical trial data have so far been published for only three SDAs to date, namely, risperidone, sertindole, and olanzapine. Of these, extensive data are available only for risperidone, showing that at doses of 4 to 16 mg/day, it is superior to haloperidol at 10 to 20 mg/day. Furthermore, risperidone, 6 and 16 mg/ day, significantly improved negative symptoms, whereas 20 mg/day of haloperidol was ineffective. Risperidone also appears to cause fewer extrapyrimidal symptoms (EPS) than haloperidol, 10 or 20 mg/day. Similar advantages of risperidone over perphenazine have also been found. A clinical trial of sertindole showed that, at 20 mg/day, it was equivalent to haloperidol, 16 mg/day, and caused fewer EPS. Olanzapine, a chemical derivative of clozapine, has also been shown to be superior to haloperidol (10 to 20 mg/day) at doses of 7.5 to 17.5 mg/day. In addition, at doses of 12.5 to 17.5 mg/day, olanzapine was found to have a signficantly superior effect on negative symptoms over haloperidol, 10 to 20 mg/day. Doses of up to 17.5 mg/day of olanzapine also caused fewer EPS than haloperidol, 10 to 20 mg/day. There was no evidence of any leukopenia in patients treated with olanzapine in this small study (N = 335). The low EPS liability of these SDAs, combined with their efficacy, suggests that SDAs should become the mainstay of treatment for schizophrenia.

Changing antipsychotic medication : Guidelines on the transition to treatment with risperidone

When treating patients with psychoses, clinicians must often consider changing their treatment from one antipsychotic agent to another. The transition may be necessary because the patient experiences serious side effects or because the existing therapy no longer controls the patients symptoms. A principal problem in changing antipsychotic agents is the potential for withdrawal symptoms resulting from discontinuation of the existing therapy. These syndromes can manifest as reemergence or worsening of psychosis, rebound or unmasked dyskinesia, and cholinergic-rebound symptoms. Withdrawal signs and symptoms may include insomnia, nausea, vomiting, anxiety, and agitation. When switching a patient to the new antipsychotic agent risperidone, the clinician can keep withdrawal symptoms to a minimum by considering the patients clinical history and current status. For some patients, abrupt withdrawal of the current antipsychotic may be possible. For others, the dose of the previous medication must be gradually reduced before risperidone is initiated. In many cases, the transition is best made by overlapping the existing therapy and risperidone.

Estrogen in experimental tardive dyskinesia

Postmenopausal women have the highest incidence of tardive dyskinesia, suggesting that loss of ovarian function may predispose to this condition. Moreover, reports have indicated that estrogens could reduce abnormal movements in tardive dyskinesia. To test the effects of estrogen in tardive dyskinesia, ovariectomized rats were treated daily for 16 days with haloperidol alone (0.5 mg per kilogram) or haloperidol plus estradiol benzoate (EB; 8μg per kilogram). Rats were then challenged with apomorphine (0.25 mg per kilogram) 4 and 10 days after cessation of the chronic treatments. Chronic treatment with haloperidol alone enhanced the response to apomorphine, whereas the combined treatment produced a synergistic response. Rats treated chronically with haloperidol and then treated daily with EB after the haloperidol treatment showed an attenuation of drug-induced stereotypy. These data indicate that estrogen may mask development of tardive dyskinesia.